病理性情感记忆相关疾病（如PTSD、药物成瘾等）是非常严重的公共卫生和社会问题，突触可塑性改变及表观遗传调控在病理性情感记忆形成中发挥重要作用。长链非编码RNA（lncRNA）可通过表观遗传调控方式参与突触可塑性相关基因的表达调节，但其在病理性情感记忆中的作用仍不清楚。本项目综合运用lncRNA芯片、生物信息学、行为学、分子药理学、分子生物学方法，采用恐惧记忆和条件性位置偏爱大鼠模型：1）研究病理性情感记忆形成过程中大鼠海马CA1区lncRNAs表达变化规律；2）选取4个与突触可塑性相关、差异表达的lncRNAs,通过构建shRNA或过表达慢病毒和海马CA1区定位注射，研究其在病理性情感记忆形成过程中的作用；3）基于SIRT6-IGFs通路，探讨lncRNA在病理性情感记忆形成中的表观调控机制。研究发现不仅为阐明病理性情感记忆的形成机制提供新的理论和实验依据，也为相关疾病治疗提供新的策略。

Pathological emotional memories (such as PTSD and addiction) are serious public health and social problem. Synaptic plasticity and the underlying epigenetic mechanism is the neural basis of formation of pathological emotional memory, and has been one of the focuses in neuroscience. Long non-coding RNA (lncRNA) is a kind of non-protein coding RNAs with the length >200 nt, which could regulate gene expression in epigenetic mechanism associated with many neurobiological processes, such as synaptic plasticity, neurogenesis and neuronal differentiation. In the preliminary study, lncRNA/mRNA chip and bioinformatics analysis were used and we obtained the differential expression profile of lncRNAs and mRNAs of hippocampal CA1 region in rats during formation of contextual fear memory. Based on these findings,using aversive memory (fear memory)and reward memory (drug reward memory) rat model, combined with molecular biological, pharmacological methods and bioinformatic analysis , we aim to investigate the role of lncRNAs in the formation of pathological emotional memory by microinjection of lncRNA and/or lncRNA-shRNA expressed-lentivirus into hippocampal CA1 region. The downstream molecular mechanism that underlies the lncRNAs' epigenetic regulation of the formation of pathological emotional memory will be focused on SIRT6-IGFs pathway. Research progress of the present study will not only contribute to elucidate the function of lncRNA in epigenetic regulation mechanism of pathological emotional memory, but also contribute to open up new avenues to develop new therapeutic methods for pathological emotional memory related disorders.

病理性情感记忆相关疾病（如PTSD、药物成瘾等）是非常严重的公共卫生和社会问题，突触可塑性改变及表观遗传调控在病理性情感记忆形成中发挥重要作用。本项目综合运用转录组学、生物信息学、动物行为学、分子生物学等技术，结合环境关联的恐惧记忆、自我给药等动物模型，重点研究了长链非编码RNA（lncRNA）、组蛋白去乙酰基转移酶（SIRT6）、DNA甲基转移酶(DNMT)等重要表观调控分子在病理性情感记忆形成、再巩固等阶段的变化规律和调控功能。获得了系列研究发现，主要包括：1）采用转录组学、生物信息学等手段、结合动物行为学技术，首次明确了环境关联的恐惧记忆形成过程中海马CA1脑区1898个mRNAs和1445个lncRNAs存在差异表达，在此基础上，进行了系统的生物信息学分析；2）基于慢病毒介导的翻译干扰技术，明确了大鼠海马CA1脑区lncRNA AJ001144参与了环境关联的恐惧记忆形成；3）采用自身给药大鼠模型，研究了DNA甲基转移酶 （DNMT）在药物成瘾记忆再巩固中的作用，明确基底外侧杏仁核脑区DNMT参与了可卡因奖赏记忆的再巩固过程；4）采用环境关联的恐惧记忆大鼠模型，明确了组蛋白去乙酰基转移酶SIRT6负性调控大鼠恐惧记忆的形成；5）在此基础上，我们进一步开展了另外一种应激性疾病——抑郁症的防治策略研究，结合慢性应激诱发的抑郁小鼠模型，明确了萝卜硫素具有显著的抗抑郁作用，孕期母源环境内分泌干扰物双酚AF暴露显著影响青春期子代小鼠的抑郁、焦虑和学习记忆等神经行为。系列研究的开展，不仅为深入了解基于lncRNA等的病理性情感记忆表观调控机制提供了直接科学依据，也为包括抑郁症在内的重要精神疾病的防治拓宽了思路。